Life Science : Ascochlorin lnhibits Growth Factor-lnduced HIF-1a Activation and Tumor-Angiogenesis Through the Suppression of EGFR/ERK/p 70S6K Signaling Pathway in Human Cervical Carcinoma Cells = Life Science : Ascochlorin lnhibits Growth Factor-lnduced HIF-1a Activation and Tumor-Angiogenesis Through the Suppression of EGFR/ERK/p 70S6K Signaling Pathway in Human Cervical Carcinoma Cells

다국어 초록 (Multilingual Abstract)

Ascochlorin, a non-toxic prenylphenol compound derived from the fungus Ascochyta viciae, has been shown recently to have anti-cancer effects on various human cancer cells. However, the precise molecular mechanism of this anti-cancer activity remains to be elucidated. Here, we investigated the effects of ascochlorin on hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression in human epidermoid cervical carcinoma CaSki cells. Ascochlorin inhibited epidermal growth factor (EGF)-induced HIF-1α and VEGF expression through multiple potential mechanisms. First, ascochlorin selectively inhibited HIF-1α expression in response to EGF stimulation, but not in response to hypoxia (1% O(2)) or treatment with a transition metal (CoCl(2)). Second, ascochlorin inhibited EGF-induced ERK-1/2 activation but not AKT activation, both of which play essential roles in EGF-induced HIF-1α protein synthesis. Targeted inhibition of epidermal growthfactor receptor (EGFR) expression using an EGFR-specific small interfering RNA (siRNA) diminished HIF-1α expression, which suggested that ascochlorin inhibits HIF-1α expression through suppression of EGFR activation. Finally, we showed that ascochlorin functionally abrogates in vivo tumor angiogenesis induced by EGF in a Matrigel plug assay. Our data suggest that ascochlorin inhibits EGF-mediated induction of HIF-1α expression in CaSki cells, providing a potentially new avenue of development of anti-cancer drugs that target tumor angiogenesis. 113: 1302-1313, 2012. ⓒ 2011 Wiley Periodicals. Inc.